The long-term effects of using opiates produce psychological and physiological adaptations within the central nervous system. This project targets the identification of new or novel mechanisms that modulate these phenomena and which may lead to new therapeutic approaches to drug abuse treatment. Evidence that NMDA receptor inactivation reduces opiate withdrawal signs and activation stimulates nitric oxide production prompted studies evaluating the relationship between reducing levels of nitric oxide production and attenuating the behavioral signs of morphine withdrawal in rats. We have extended initial studies to evaluate newer inhibitors of the enzyme nitric oxide synthase (NOS), which exhibit higher in vitro selectively for the isoforms of NOS, in order to determine how this selectivity translates into in vivo efficacy for reducing signs of opiate withdrawal. We have concluded that the nitric oxide produced by the constitutive isoforms of NOS rather than inducible NOS modulates morphine withdrawal. Two nitro indazole NOS inhibitors were unique because they were efficacious in reducing signs of opiate withdrawal and did not elevate blood pressure as did other NOS inhibitors. The use of NOS inhibitors to attenuate opiate withdrawal is different from any non-opioid approach presently used clinically, such as clonidine, which reduces withdrawal, but also produces hypotension. Preliminary studies are assessing the potential of NOS inhibitors to reverse existing tolerance in rats because an agent that could both reduce tolerance and attenuate withdrawal would provide a new concept for treatment of long-term opioid use. A second study explored the pharmacokinetics of morphine administration and abuse potential. Experienced long-term, but non- dependent heroin users reported more pronounced subjective effects, reflecting the positive, rewarding properties of a 10-mg, intravenously administered dose of morphine, following rapid rather than slow intravenous administration. These data indicate that faster rates of administration produce effects associated with greater abuse liability. A concurrent physiological measure, pupillary constriction, did not vary with the rate of morphine administration indicating an apparent dissociation of subjective and physiological responses. The association of a greater subjective effect with a faster rate of opiate administration agrees with the histories of the subjects themselves and with street lore that has been acknowledged for decades, but heretofore not tested under controlled conditions.